Materials and Food Additives Free of Endocrine Disruptive Activity

ABSTRACT

The present invention describes plastic materials and food additives that are free or substantially free from endocrine disruptive chemicals. The plastic materials may be used in products which are exposed to individuals in which endocrine disruptive activity is particularly disadvantageous, such as baby bottles, baby toys, food containers, medical containers, animal cages and medical products. The food additives may be used in food products that are ingested by individuals in which endocrine disruptive activity is particularly disadvantageous, such as newborns or the physically infirm. The present invention also describes a series of assays which, when performed in combination, provide a novel method for determining the presence of endocrine disruptive activity.

PRIORITY STATEMENT UNDER 35 U.S.C. §119 & 37 C.F.R. §1.78

This application is a continuation of, and incorporates by reference inits entirety, application Ser. No. 10/852,026, filed May 24, 2004, whichis a continuation of application Ser. No. 10/143,385, filed May 10,2002, also incorporated by reference in its entirety, which claimspriority based upon prior U.S. Provisional Patent Application Ser. No.60/290,595 filed May 10, 2001 in the name of George Bittner, entitled“Materials Void of Adverse Hormonal Activity and Method For Determiningthe Presence of Hormonally Active Substances in Materials.”

FIELD

The present invention relates, generally, to the field of plastics and,more specifically, to plastic materials and food additives that aresubstantially free of endocrine disruptive chemicals. The presentinvention also relates to methods for detecting endocrine disruptiveactivity.

BACKGROUND

There is increasing evidence that certain synthetic and naturalchemicals, called endocrine disruptors, may act as agonists orantagonists to estrogens or androgens and may interfere in multiple wayswith the action of thyroid hormones. For example, endocrine disruptorscan mimic or block chemicals naturally found in the body, therebyaltering the body's ability to produce hormones, interfering with theways hormones travel through the body, and altering the concentration ofhormones reaching hormone receptors. Although relatively few chemicalshave been examined for their endocrine disruptive effect, thosechemicals that have shown such an effect are increasingly found incommon food and plastic products.

Endocrine disruptors include chemicals such as, for example,polychlorinated biphenyls (PCBs), dioxins and furans. These chemicalsare found environmentally in insecticides, herbicides, fumigants, andfungicides that are used in agriculture as well as in the home. Otherendocrine disruptors are found in common chemicals such as detergents,dental amalgams and resins that coat the inside of tin cans. Inaddition, research has found that, because the polymerization processused to make plastics is not complete, unpolymerized monomers withestrogenic activity can migrate out of plastics resulting in deleteriousestrogenic, carcinogenic or toxic effects in humans and other species.

By way of example, di(2-ethylhexyl)phthalate (DEHP) is a plasticizerthat is a colorless liquid with almost no odor. DEHP is commonly used inproducing polyvinyl chloride (PVC) plastic products like toys, vinylupholstery, shower curtains, adhesives, and coatings. PVC plastic maycontain up to 40% DEHP. DEHP, an estrogen-mimicking chemical, has beenfound to leach from these plastics, thereby creating problems with thematerials in contact with the plastic. For example, DEHP has been foundto leach from intravenous bags and tubing into the blood and medicationsbeing administered to patients. Exposure to DEHP through intravenousbags and tubing presents a health risk that could be avoided through theuse of a plastic material that does not contain endocrine disruptivechemicals.

Similarly, bisphenol A is a monomer used to synthesize a number ofplastics, such as polycarbonates, epoxy, phenoxy and polysulfonepolymers, and is released in significant amounts when these plastics areexposed to water, particularly when heated. Bisphenol A has been shownto possess deleterious estrogenic activity. Nevertheless, plasticsmanufactured with bisphenol A, such as polycarbonate, are commonly usedfor food and beverage containers, baby bottles, baby toys, microwaveablecontainers and medical items.

Molecular Mechanisms by which Endocrine Disruptors Produce EstrogenicActivity

Endocrine disruptors and natural estrogens share a common mechanism ofaction. In normal cases, estrogenic activity is produced by bindingnatural estrogen to an estrogen receptor (ER) within the nucleus of thecell, followed by transcriptional activation of these occupied ERs. Whenendocrine disruptors are present, normal estrogenic activity issupplanted when endocrine disruptors bind an ER, causing transcriptionalactivation of the ER even though no natural estrogen is present.Similarly, antiestrogenic activity is produced by endocrine disruptorswhich bind to ERs but which do not subsequently activate the occupiedER. Finally, selective estrogen receptor modulators (SERMs) bind to ERs,but subsequently activate cellular responses that differ from thoseactivated by the natural estrogens. In general, all but a very smallnumber of molecules that bind to ERs produce some activation of thereceptors, as either estrogens or as SERMs. In other words, there areseveral potential mechanisms by which food antioxidants and otherchemicals produce endocrine disruptive activity, but the most common,and best understood, mechanism is via binding to estrogen receptors,thus mimicking the action of natural estrogens.

Effects of Endocrine Disruptors on Human Health

Researchers are exploring the possible link between exposure toendocrine disrupters and breast cancer, testicular cancer, and low spermcount. Deleterious estrogenic effects in humans occur atenvironmentally-relevant concentrations and include abnormal brainmaturation leading to developmental problems or pathologies such as, forexample, learning disabilities, attention disorders, abnormalities inmotivation, emotion, cognitive development and reproduction, increasesin aggressive behavior and changes in sexual orientation. Although theresearch regarding the effects of these chemicals on human health isjust beginning, studies have already been completed on the effect ofprenatal exposures to endocrine disruptors on child behavior that havedocumented developmental injury.

When tested in animal model systems, endocrine disruptors producedeleterious estrogenic effects at concentrations less than thoseconcentrations that are released by certain plastics. For example,research has found that very low dosages of endocrine disruptors exhibitbehavioral effects on rodents including, for example, learningdisabilities, disorders of attention, motivation, emotion, cognitivedevelopment, and changes in sexual orientation and aggressive behavior.Other effects include alterations of reproductive organs of infant andadult males and females such as reduced sperm counts, prostateenlargement, ovarian and uterine dysfunction, and the rate of growth andtime to sexual maturation.

As with many hormones, the effects described above are often moredramatic in fetal or developing mammals than in adults. In adults,hormones mainly regulate ongoing physiologic processes. As a result,adult bodies can sometimes compensate or recover from temporary hormonalmodulation. Hormonal effects in the fetus are much more profound becausethey affect gene expression that governs development of organs as wellas lifelong hormonal traits, such as receptor numbers and hormonalproduction. Accordingly, in the case of endocrine disruptors and otherdevelopmental toxicants, the timing of exposure may be more importantthan the dose.

Concern over the effects of endocrine disruptors has increased recentlyas a result of research showing that plastics commonly used in the home,such as, for example, baby products, food containers and microwaveableproducts, readily leach endocrine disruptive chemicals. The ubiquity ofsuch plastic items almost certainly contributes to deleterious hormonaleffects on human development, beginning prenatally and continuingthrough puberty and into adulthood. For example, recent data show thatlevels of bisphenol A in human umbilical cords are 0.2 to 2micrograms/kg which is consistent with the levels of bisphenol Areported to leach from can linings and plastic baby bottles intovegetable products eaten by babies. Research has shown that a typicaldaily intake of 700 ml of formula containing 5 ppb bisphenol A from ababy bottle by a 7 kg baby would result in a daily dose of bisphenol Aof 0.5 micrograms/kg/day. Furthermore, deleterious developmental changeshave been reported in snails, fish, frogs, and rodents at 0.5 to 2micrograms/kg/day. While it is unlikely that randomized trials will everdirectly examine the deleterious developmental effects of bisphenol A onhuman infants, it is likely that such deleterious effects are producedin humans since basic endocrine mechanisms are not markedly different inrodents and humans.

In part as a response to the recent concern over the effects ofendocrine disruptors, the United States government and foreigngovernments have become active in the testing and regulation ofendocrine disruptors. In the United States, the Food Quality ProtectionAct of 1996 requires that the United States Environmental ProtectionAgency to develop an endocrine disruptor screening program. The SafeDrinking Water Act of 1996 authorizes the United States EnvironmentalProtection Agency to screen endocrine disruptors found in drinkingwater. Outside the United States, a number of countries have adoptedregulations of endocrine disruptors. For example, the European Unionbanned the use of phthalates and PVC, known endocrine disruptors, intoys for children under three years of age.

Plastic Monomers and Additives

Plastics are made from monomers that are synthesized into polymers,typically by the application of heat, pressure and, in certain cases,catalysts. The most common monomers from which plastics are made areshown in Table 1.

TABLE 1 Plastic Production Monomer Exhibits Estrogenic (EA) orCarcinogenic (CA) Monomer Polymer Acronym Activity Ethylene PolyethylenePE² NT (LDPE, HDPE, LLDPE) Vinylchloride Polyvinylchloride PVC CAPropylene Polypropylene PP NT Styrene Polystyrene PS NT Bisphenol APolycarbonate^(1,3) PC EA (Epoxy, Polysulfone, Phenoxy, etc Polymers)Terephthalic acid + Polyethylene, PET EA ethylene glycol terephthalateSources for Table 1: EDSTAC, 1998; NRC, 1999; NTP, 2000; Society forPlastics Industry. NT-To Applicant's knowledge this chemical has not yetbeen tested for estrogenic activity. ¹Polymer can be formulated toproduce plastics with vastly different characteristics. ²PE can besynthesized into low-density PE (LDPE), high-density polyethylene(HDPE), and linear low-density PE (LLDPE). ³Monomers are incompletelypolymerized and may migrate out of the final plastic product.

Of the monomers used to produce common plastics, polyethylene (PE) ismost frequently used because it is inexpensive to synthesize and hasextremely versatile properties. Low density PE (LDPE) and linear lowdensity PE (LLDPE) are also widely used, predominantly for extrudedmaterials and film materials which are commonly used to wrap foodproducts. High density PE (HDPE) is used in applications that involvecontact with either food products or portable water, such as, forexample, film, plastic bottles, and plastic pipe. Many plasticcontainers for carbonated beverages are now made of polyethyleneterephthalate (PET), an excellent barrier material against the migrationof carbon dioxide through the container.

Numerous additives are introduced after the synthesis of plastics toenhance their properties. For example, antioxidants are added toincrease the useful life of PE and other plastics by preventing, or atleast minimizing, the degradation of oxygen which can often causebreakage of molecular chains leading to other undesirable effects suchas, for example, discoloration, loss of surface gloss, surface cracking,and lowering of tensile strength. Furthermore, plastics are typicallyprocessed into useful shapes at temperatures in excess of 150°centigrade which can lead to thermo-oxidative degradation of molecularweight, ductility, and strength. Table 2 lists some common antioxidants,all of which, with the possible exception of organo-phosphites andthio-ethers, have estrogenic, carcinogenic or other toxic effects.

TABLE 2 Some Common Antioxidants Predicted Estrogenic PredictedCarcinogenic Antioxidants Activity or Other Toxic Effects (di)Butylhydroxy toluene (BHT) Yes Yes Hindered Phenols Yes NT Organo-PhosphitesNT NT Thio-esters NT NT 2° Acrylamines NT Yes Sources for Table 2:EDSTAC, 1998; NRC, 1999; NTP, 2000; Society for Plastics Industry. NT-ToApplicant's knowledge this chemical has not yet been tested forestrogenic activity.

Depending on the material and its desired use, additives other thanantioxidants are also used in plastic processing. For example, variouspigments including, for example, lead chromates, lead molybdates, leadsulphteranges, chromium oxides, ferric ammonium ferrocyanide, carbonblack and phthalo blues are used to add color to PE and other polymers.Common pigments are found in Table 3. Many of these pigments exhibitendocrine disruptive activity or other toxic effects.

TABLE 3 Some Common Pigments Predicted Predicted Carcinogenic PigmentsEstrogenic Activity or Other Toxic Effects Lead chromate Yes Leadmolybdate Yes Lead sulphterange Yes Chromium oxides Yes Ferric ammoniumYes Ferrocyanide Yes Carbon black No Phthalo blues Yes Sources for Table3: EDSTAC, 1998; NRC 1999; NTP, 2000; Society for Plastics Industry.

Other classes of plastic additives include plasticizers and stabilizers.For example, esters of phthalic acid, one of the most ubiquitousplasticizers for PVC compounds, all exhibit estrogenic disruptiveactivity and are frequently used in high concentrations, often 40-80% byweight, in plastic materials. This is extremely troublesome because mostplasticizers are quite mobile at ambient conditions and, whenchild-oriented products are made from these materials, children mayingest significant amounts of these compounds when they “taste” theirsurroundings.

Stabilizers on the other hand, inhibit or reduce damage caused byelectromagnetic radiation to PEs and other polymers. Thermal stabilizersfor PVC include barium-cadmium soaps, organo-tin compounds, leadcompounds, and cadmium-zinc soap. Additives that contain lead andcadmium are clearly toxic. Many of the most common ultravioletstabilizers for PE such as, for example, benzothiazoles andbenzophenones have exhibited endocrine disruptive activity and haverather low molecular weight. Such low molecular weight (1000 daltons)stabilizers are routinely added to PE and are sufficiently mobile tomigrate by diffusion from the plastic to the environment. Commonstabilizers are found in Table 4.

TABLE 4 Some Common Stabilizers Predicted Predicted CarcinogenicStabilizers Estrogenic Activity or Other Toxic Effects Barium-cadmiumsoaps Yes Organo-tin compounds No Lead compounds Yes Cadmium-zinc soapsYes Benzothiazoles Yes Benzophenones Yes Sources for Table 4: EDSTAC,1998; NRC, 1999; NTP, 2000; Society for Plastics Industry.

Some plastic additives are widely used in the United States in spite oftheir known endocrine disruptive activity. For example, bisphenol A is amonomer used to synthesize various plastics such as, for example, PCs,epoxy, phenoxy, and polysulfone polymers and is released in significantamounts when the polymer is exposed to water, particularly when heated.Although bisphenol A has been demonstrated to exhibit endocrinedisruptive activity, PC products are commonly used for food and beveragecontainers, baby bottles, baby toys, microwaveable containers, andmedical items. PC production has rapidly increased in the United Statesand, consequently, bisphenol A is now one of the top 50 chemicalsproduced in the U.S.

Due to federal regulations and commercial concerns, most monomers oradditives with carcinogenic or other lethally toxic effects are notfound in plastics routinely contacted by humans or that contact food.The U.S. Food and Drug Administration (FDA) has long recognized theproblem of migration of chemicals out of plastics and other products andhas strictly regulated the antioxidants and other agents in plasticcompounds that contact food. The FDA has required that such additives betested for carcinogenic properties and other acute toxic effects. Lesstoxic stabilizers such as tin soaps are approved by the FDA for foodcontact, but less expensive, albeit toxic, stabilizers such as, forexample, barium, cadmium, and lead compounds, are approved for use inother applications such as electronics parts that do not contact food.Although tested for carcinogenic activity and acute toxicity, chemicalsused in plastics that contact humans directly or that contact food havenot been tested for estrogenic activity and, as a result, the disruptiveactivity has not yet been regulated. Furthermore, the formulations usedto manufacture plastics usually are not required to be revealed to othercompanies, consumers or governmental agencies. Even when themanufacturer divulges the primary monomer or polymer used in a plastic,it rarely reveals all additives used in the formulation.

The United States Food Quality Protection Act requires that chemicals betested and regulated for endocrine disruptive activity. In furtherancethereof, a multimillion-dollar request for proposal for validation oftests on endocrine disruptive activity has recently been awarded by theU.S. Environmental Protection Administration. The need for, andregulation of, safer plastics with less endocrine disruptive activity isnow being driven by well-documented scientific findings.

Numerous products have been affected by regulations or consumer concernsin other developed countries. For example, several European Unioncountries recently banned the use of phthalates and PVC plastics in toysfor children under three. Consequently, plastic bottles or teethingrings in Europe, Japan and the U.S. are no longer made from PVC due toconcerns by the public and commercial retailers about the deleterioushealth effects of phthalates and PVC. As a second example, the use ofmany PC products such as, for example, baby bottles and dishes, hasrecently decreased dramatically in Japan due to public awareness thatthese PCs release bisphenol A whose estrogenic activity has potentiallydeleterious effects on reproductive functions and many otherphysiological systems in humans.

Although the concern over the presence of endocrine disruptive chemicalsin plastics is escalating, no plastic product on sale in the UnitedStates or international market has been demonstrated to be free ofendocrine disruptive chemicals. Therefore, the need remains for aplastic material that is substantially free of endocrine disruptivechemicals.

Food Additives

More than 2,800 different food additives are routinely used to maintainproduct freshness and quality and help retard physical, chemical andbiological deterioration. Table 5 lists some commonly used foodadditives and their intended function.

TABLE 5 Commonly Used Food Additives and Intended Function AdditiveIntended function Examples Antimicrobial Prevent microbial Sodiumbenzoate, calcium preservatives growth propionate, potassium sorbate,sodium nitrite Antioxidants Prevent rancidity BHT, BHA, propyl gallate,tocopherols Flavor Supplement, enhance MSG, disodium inosinate,enhancers or modify original flavor disodium guanylate SynergistsIncrease the effects of Citric acid, tricalcium phosphate other foodadditives and other phosphates, ascorbic acid

Antioxidants are one of the most important and most widely used foodadditives. The oldest and most common antioxidants that are deemedsuitable for food contact service belong to a class of materials knownas hindered phenols. The most ubiquitous of these is BHT. Since 1949,BHT has been widely used as an antioxidant food additive in large partbecause it is very inexpensive and because it was routinely assumed tobe non-toxic. BHT works by intercepting and reducing free radicals thatare associated with the oxidation process. However, primary datasuggests that BHT exhibits endocrine disruptive activity. BHT istherefore almost certainly unsuitable as an antioxidant in foods.

Table 6 lists 12 common food antioxidants. Some antioxidants such as,for example, BHA, BHT, tocopherols, TBHQ, gallates and THBP, are widelyused due to their overall efficacy. Others are “natural” antioxidantsisolated from plants, although they are less commonly used in themanufacture of food products at present. The estrogenic activity of foodantioxidants has not yet been examined, but many food antioxidants wouldbe expected to exhibit estrogenic activity because they contain aphenolic ring. Since many estrogenic chemicals have effects at picomolarto nanomolar levels and antioxidants are often added to foodstuffs inmicromolar to millimolar concentrations (i.e. 1000× greater), suchestrogenic antioxidants could be a significant health hazard,particularly to a developing fetus. The need exists, therefore for foodadditives substantially free of endocrine disruptive activity.

TABLE 6 Antioxidants Permitted in Foods in the United States # of #—OH^(B) Benzene (on QSAR^(C) ADI^(D) Primary Antioxidants Rings^(A)benz) RBA Use or Origin Approved 1. Butylated 1 1 (1) yes, −5 Fats andoils, 0-0.5 mg/kg hydroxyanisole (BHA) confectioneries, food-  0.01-0.1% coating material, and 2.Butylated 1 1 (1) yes, −5 Low fatfoods, fish 0-0.125 mg/kg hydroxytoulene (BHT) products, packaging0.005-0.02% materials⁶ 3. Tocopherols 1 1 (1) yes Major lipid soluble0.15-2 mg/kg antioxidant 4. Tert-Butylhydroquinone 1 2 (2) yesStabilizes fats, oils, 0-0.2 mg/kg (TBHQ) confectionery products, etc 5.Propyl gallate 1 3 (3) no Stabilizes animal fats and 0-2.5 mg/kgvegetable oils, meat  0.001-0.01%; products, spices and       0.1%snacks (chewing gum base) 6. 2,4,5-Trihydroxy- 1 3 (3) no StabilizesVitamin A,      0.02% butyrophenone (THBP) oils, used in packagingMigration < material⁶     0.005% 7. Curcumin^(E) 2 2 (2) yes fromtumeric 8. Catechin^(E) 2 4 (4) yes, −2.10 from tea 9. Sesamin^(E) 2 0(0) ? from sesame seeds 10. Sesamolin^(E) 2 0 (0) ? from sesame seeds11. Carnosine^(E) 0 1 (0) ? from rosemary 12. Glycyrrhizic Acid^(E) 0 4(0) ? from licorice ^(A)# of benzene rings in this antioxidant.^(B)Number of —OH groups (number of —OH groups on benzene rings) in thisantioxidant. ^(C)yes, no: prediction of significant binding abilitybased only on number of OH and number of OH groups on benzene ringsabove; −#: Negative log relative ERα binding affinity (RBA) with respectto 17β-estradiol (RBA = 0) according to preliminary data calculated by acomplete QSAR analysis. An antioxidant with an ERα RBA more negativethan −6 should have little or no ability to bind to ERα or ERβ. ^(D)ADI:Average Daily Intake gives the recommended daily dietary allowance forthese antioxidants. ^(E)Good toxicological data does not exist for these“natural” antioxidants. ^(F)Antioxidants may be added directly topackaging materials rather than the food product itself. Theeffectiveness of the antioxidant depends on its rate of migration to thefood material and the antioxidant vapor pressure. Breakfast cereals andbakery goods are often packaged in this manner, permitting largerquantities of antioxidants to be added to the package liner, provided nomore than the legally allowed concentrations migrate into the product.

Testing

The process of obtaining an approval for food additives for human use isregulated by Center for Food Safety and Applied Nutrition (CFSAN) at theFDA under the Federal Food Drug and Cosmetic Act. The requiredtoxicological studies include absorption, metabolism, and excretionstudies, acute toxicity, short-term studies, long-term andcarcinogenicity studies, reproduction, skin toxicity, and mutagenicity.Some of the additional recommended studies include neurotoxicity andimmunotoxicity. Despite the extensive number of studies required byCFSAN, the current toxicological studies do not adequately addressendocrine disruptor issues, in part because the endpoint measurementsand the doses at which LD50 or carcinogenic effects and endocrinedisruptive effects are observed are markedly different and in partbecause different assays are needed.

A vast majority of the 80,000 chemicals currently sold on the U.S. andinternational market have not been tested for estrogenic effects. Onesignificant reason for the lack of testing has been the lack of areliable test procedure for testing the presence of endocrine disruptiveactivity. The need exists, therefore for a reliable, comprehensive testfor the presence of endocrine disruptors in plastics and foods.

Unique/Innovative Approach in Development of New Plastic Formulations

As discussed above, plastics synthesized from bisphenol A, such aspolycarbonate and other plastics, have deleterious estrogenic activity,but are now commonly used for food and beverage containers, babybottles, baby toys, microwaveable containers, and medical items. Hence,there is a demand for new plastic formulations that lack biologicallydetectable estrogenic activity but retain the useful characteristics ofcurrent plastics.

In one embodiment of the present invention, a monomer is polymerized toform a polymeric material that is substantially void of endocrinedisruptive chemicals. This polymeric material may be, for example,polyethylene or polypropylene. Articles may be made form this polymericmaterial such as, for example, baby bottles, baby toys, medical devices,food containers, beverage containers, medical containers and animalcages.

In another embodiment of the present invention, a monomer is polymerizedto form a polymeric material, such as polyethylene or polypropylene,with the addition of only an antioxidant known not to contain endocrinedisruptive materials such as, for example, propyl gallate, octylgallate, dodecyl gallate, ethoxyquin, carnosine, glycyrrhizic acid,sesamin, sesamolin, monoisopropyl citrate and thiodiproprionic acid.Once again, an article such as that described in the foregoing paragraphmay be made from this material.

Polymeric materials substantially void of endocrine disruptive chemicalsmay be prepared by processing, for example, an ethylene monomer withitself to form a polyethylene polymer and subsequently converting thatpolyethylene polymer into the desired material such as, for example, anextruded film, an injection molding blank or other material. Similarly,a propylene monomer may be processed with other propylene monomers toform similar articles. In another embodiment, polymeric materialssubstantially void of endocrine disruptive chemicals may be prepared bypolymerizing, for example, an ethylene monomer with an antioxidant knownnot to contain endocrine disruptive materials such as, for example,propyl gallate, octyl gallate, dodecyl gallate, ethoxyquin, carnosine,glycyrrhizic acid, sesamin, sesamolin, monoisopropyl citrate andthiodiproprionic acid to form a polyethylene material and subsequentlyconverting that polyethylene polymer into the desired material such as,for example, an extruded film, an injection molding blank or otherarticle. A propylene monomer can be substituted for the ethylene monomerin the foregoing example to create a polypropylene materialsubstantially free of endocrine disruptive materials.

The already daunting task of developing these new plastic formulationsis made more complex by fact that the chemistry of effective additivesthat lack detectable estrogenic activity has not yet been explored. Thedevelopment of new formulations that are commercially attractive andthat lack biologically detectable estrogenic activity requiresinnovative combinations of scientific knowledge from several disparatescientific fields: endocrine physiology, molecular biology,environmental health science and polymer chemistry. The only way for toreliably determine that plastic formulations do not have biologicallydetectable estrogenic activity is for all chemicals in a plasticformulation, as well as those chemicals which leach from the plastic, totest negative for such activity in a series of state-of-the-art assays.The only way to determine the effectiveness of any additives lackingdetectable estrogenic activity is to perform shelf life, or durability,studies, perhaps in combination with additional studies on plasticsheets that are exposed to harsh conditions such as extreme temperature,UV and microwave radiation, and chlorine exposure.

SUMMARY

The present invention relates, generally, to the field of plastics and,more specifically, to plastic materials and food additives that aresubstantially free of endocrine disruptive chemicals. Specifically, thepresent invention provides for the use of certain monomers, or thecombination of certain monomers and additives, to make plasticcompositions and products which are substantially free of endocrinedisruptive chemicals and are therefore useful in products andapplications where no endocrine disruptive effects are desired.

The present invention also relates to the field of food products andfood additives and, more specifically, to food products and foodadditives that are substantially free of endocrine disruptive chemicals.

The present invention also relates to methods for detecting endocrinedisruptive activity and, more specifically, to a series of assays which,when performed in combination, provide a novel method for determiningthe presence of endocrine disruptive activity.

1. An article made from a polymeric material substantially void ofendocrine disruptive chemicals comprising a monomer wherein said monomeris polymerized to form a polymeric material substantially void ofendocrine disruptive chemicals, wherein said article is selected fromthe group consisting of baby bottles, baby toys, medical devices, foodcontainers, beverage containers, medical containers and animal cages. 2.A polymeric material substantially void of endocrine disruptivechemicals comprising a monomer wherein said monomer is polymerized inthe presence of a non-organo-phosphorus antioxidant to form a polymericmaterial substantially void of endocrine disruptive chemicals.
 3. Thepolymeric material recited in claim 2 wherein said monomer is selectedfrom the group consisting of ethylene and propylene.
 4. An article madefrom the polymeric material as recited in claim 2.